Boosting activity of the heart protective enzyme HACE1

Substrate capture analysis and activity enhancement by deep mutational scanning of HACE1, a stress response ubiquitin ligase with multiple functions in cardiovascular protection

Dr Stefan Bagby and colleagues at the University of Bath are working how to increase the activity of a protective enzyme called HACE1 in the heart. HACE1 protects the heart against high pressures and oxidative stress. When HACE1 is absent or reduced, heart failure progresses faster. Because HACE1 is protective, Dr Bagby and colleagues want to promote the abilities of HACE1 to target and modify the right proteins. But little is known about how HACE1 recognises and interacts with other proteins. In this project, Dr Bagby will use biophysical and biochemical techniques to work out how HACE1 interacts with key target proteins to keep hearts healthy. He will use cutting edge technologies to rapidly make and test hundreds of thousands of slightly different variants of HACE1. He will find out if each alteration increases or reduces HACE1 activity and specificity. This research could reveal how to make HACE1 more selective and active in the proteins it targets. Being able to increase the protective ability of HACE1 could help us better prevent or treat heart disease.